In our study of non-cognitive neuroimaging phenotypes in healthy siblings, we focused primarily on cognitive function as a target phenotype related to genetic risk for schizophrenia. Patients have shown to manifest prominent abnormal emotional states. In fact, emotional dysfunction has been viewed as a cardinal feature of schizophrenia;but it is unknown whether it represents a heritable phenotype related to risk for schizophrenia or whether it is related to disease state. To test this, we studied patients with schizophrenia, healthy siblings and normal controls with fMRI while the participants performed a facial emotion information processing task which measures amygdala responsivity to negative emotional stimuli. As an experimental control, we used the N-Back working memory task, which has been shown to elicit cognitive abnormalities in healthy siblings of patients with schizophrenia. Patients with schizophrenia showed a deficit in amygdala reactivity to negative emotional stimuli and an alteration in the functional interaction between the amygdala and subgenual cingulate. In contrast, the siblings showed a pattern that was not different from normal controls. During the N back test, both patients with schizophrenia and their siblings showed a pattern of inefficient engagement, consistent with earlier evidence that this pattern is related to genetic risk for schizophrenia. Our results suggest that although a deficit in face emotion processing, likely related to emotional dysfunction, is a characteristic feature of schizophrenia, it is more likely related to the disease state, than to inherited risk factors for schizophrenia, such as prefrontal cortical deficits. These results again demonstrate the value of the extensive characterization of healthy siblings. In another study, we looked at volumetric differences in various brain structures between patients with schizophrenia and normal subjects, including their healthy siblings, which have been reported in numerous MRI studies. Recent evidence suggests that similar volumetric changes may be found in at risk subjects, including healthy relatives and pre-psychotic and prodromal patients. However, in these earlier and generally small studies the impact of confounding variables that may affect MRI measures of brain volume, including psychotropic drugs, substance and alcohol abuse, smoking, and head injury have generally not been taken into account. We performed two large studies of structural MRI measures in our healthy siblings of patients with schizophrenia to test the hypothesis that structural brain abnormalities measured with MRI are related to genetic risk for illness. In the first study, MRI scans from 169 patients with schizophrenia, 213 of their unaffected siblings, and 212 healthy volunteers were evaluated using optimized VBM. Patients with schizophrenia had significant regional gray matter decreases in the frontal, temporal, and parietal cortices compared with healthy volunteers. While their unaffected siblings tended to share gray matter decreases in the medial frontal, superior temporal and insular cortices, these decreases were not significant after correction for multiple comparisons. The second study involved measurements of cortical thickness using a surface based approach in 196 normal controls, 115 affected patients with schizophrenia, and 192 unaffected siblings. Node-by-node mapping statistics revealed widespread thickness reductions in the patient group, most pronounced in the frontal lobe and temporal cortex. Unaffected siblings, however, did not significantly differ from normal controls at the chosen conservative threshold. Both studies found evidence of heritability of cortical thickness comparison of patients, siblings and controls cortical measurements but no increased association with risk for schizophrenia. These data argue that while siblings may share subtle regional gray matter decreases with their affected sibling the pattern of regional differences may not be useful as a target intermediate phenotype for schizophrenia. Our results suggest that to the extent that the structural brain abnormalities associated with schizophrenia are about risk and not manifest illness, they reflect the non-genetic components of risk, such as early developmental environmental factors, or they reflect as yet undefined gene-environment interactions.